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In the eyes of chemists, nature is really amazing.

Many complex natural products have good pharmacological activities, and people have always wanted to simulate the magical power of nature to synthesize these compounds. But for chemists, artificial synthesis is often extremely difficult due to the complexity of the structure of these compounds.


In the 1960s, American chemists isolated crude extracts of paclitaxel from the bark and wood of Pacific fir. However, due to the extremely low content of paclitaxel in the Pacific fir, about 6 trees need to be cut down to get 500 mg of paclitaxel, which means that hundreds of trees will be cut off only for drug experiments. This is really not an efficient method, so chemists began to study the total synthesis of paclitaxel. However, the success of the total synthesis strategy is still insufficient to support the drug development and subsequent commercial production of paclitaxel.

The emergence of semi-synthetic strategies has made the commercialization of paclitaxel possible. In 1992, Robert Holton Labs designed a 4-step synthetic route to paclitaxel from 10-DAB. In 1994, Bristol-Myers Squibb successfully achieved the commercial production of paclitaxel based on this synthetic route, and paclitaxel quickly became a heavy drug.


Paclitaxel is undoubtedly fortunate, but not every complex natural product has the same fate as paclitaxel. Even now, chemical synthesis is still a major factor limiting the commercial production of some highly effective drugs.


Ocean gift


In 1986, Japanese scientists Hirata and Uemura isolated a polyether macrolide containing only C, H, and O atoms from the sponge Halichondria okadai. They named this extremely complex natural product as Halichondrin B.


The National Cancer Institute conducted a systematic evaluation of the activity of halichaxin B based on 60 cancer cell lines, and found that halichaxin B has a strong in vitro antitumor activity. At the same time, the researchers also found that the anti-cell proliferation mechanism of halichondrin B is similar to that of anti-tubulin drugs, but its biochemical mechanism is slightly different. Soft sponge B can also inhibit the depolymerization of tubulin, but the binding site and mechanism of action are significantly different from other inhibitors.


Due to its strong anti-tumor activity and unique mechanism of action, the compound has rapidly attracted the attention of academics and pharmaceutical companies. However, the amount of sample extracted from nature as a natural product is very limited. One ton of sponge can only extract about 400 mg of halichaxin B, and only 10 g is needed for clinical development. This severely constrained the development of this drug, and scientists at that time quickly thought of solving the problem of insufficient production of halichondrin B through total synthesis.


However, the total synthesis of halichondrin B is also extremely difficult because the molecular structure of halichondrin B is very complex and contains 32 chiral centers, which means that there are more than 4 billion isomers of halichondrin B. So many chiral centers pose a significant obstacle to the design of synthetic routes, chiral control during synthesis, and purification processes after reactions.


Despite the difficulties, Harvard’s Yoshito Kishi Lab accepted the challenge. The laboratory uses a convergent polymerization strategy to break down the soft spongin B into four fragments, which are then joined into the target molecule. In 1992, they reported for the first time the full synthesis strategy of halichondrin B.


Although Kishi Laboratories achieved full synthesis of halichaxin B, and later some laboratories further optimized the total synthesis strategy of halichondrin B. However, it is obvious that due to the difficulty of synthesis and high cost, it is still difficult for them to carry out subsequent research and development and commercial production of halichondrin B based on the synthesis strategy.


However, in fact, the all-synthesis route of the soft-sphingidin B reported at the time had a great advantage, that is, the aggregation polymerization strategy adopted allowed modification of each fragment, which made an important promotion for the study of the structure-activity relationship of the compound. effect.


Therefore, Kishi Laboratories began to cooperate with the medicinal chemist of Eisai to derivatize the compound structure of halichondrin B based on the previous total synthesis strategy, in order to find the pharmacophore of halichondrin B and study its structure-activity relationship. .


From a medicinal point of view, the halichondrin B macrolide fragment is more likely to be a carrier for its anticancer activity than the polyether fragment, since the functional group of the macrolide fragment is more diverse, and the polyether fragment The structure is relatively simple. This suggests that the simplification of the structure of the halichonin may not significantly affect its anti-tumor activity.


Medical chemists have also confirmed that removal of most of the polyether fragments remains capable of maintaining the antitumor activity of such compounds. It is clear that the molecular size of the compound can be greatly reduced after removal of most of the polyether fragments. After a series of structural modifications, the medicinal chemist finally obtained the compound Eribulin which is smaller in size, softer in synthesis and better in drug-making than the soft sponge compound B.

Phase III clinical trial (Study 305) showed that Eribulin was able to prolong the overall survival of patients with metastatic breast cancer (13.2 vs 10.6 months) compared with the control group, with an objective response rate of 11% and a median response time of 4.2. month. On November 15, 2010, the FDA approved Eribulin for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens for metastatic disease (chemotherapy regimens should include anthracyclines or paclitaxel).

In recent years, the incidence of breast cancer in China has increased year by year. Although breast cancer screening contributes to early detection of the disease, approximately 10% of patients still have locally advanced or metastatic breast cancer at the time of diagnosis.


The treatment of metastatic breast cancer is not easy. In addition to surgery for in situ cancer and adjuvant radiotherapy, most patients will receive multi-line chemotherapy, hormone therapy or targeted drug therapy. Chemotherapeutic drugs for the treatment of metastatic breast cancer can generally be divided into several types: microtubule inhibitors (taxanes, vinblastines and epothilones), anthracyclines, and anti-metabolites such as gemcitabine and fluorouracil. .


For patients with metastatic breast cancer, although these chemotherapy drugs can produce a certain therapeutic effect at the beginning, patients usually develop resistance to chemotherapy drugs. Therefore, the emergence of new, non-taxane microtubule inhibitors such as Eribulin will provide new possibilities for the treatment of this part of patients.

In addition to metastatic breast cancer, Eribulin also has a major impact on the treatment of liposarcoma. In a clinical trial of 143 patients with liposarcoma, Eribulin significantly prolonged median survival (15.6 vs 8.4 months) and median progression-free survival (2.9 vs 1.7) compared with dacarbazine. month). On January 28, 2016, the FDA approved Eribulin for the treatment of patients with advanced or metastatic liposarcoma who had previously been treated with an anthracycline regimen.

Although Eribulin’s compound patents will expire on June 19, 2019, there are only a handful of generic companies that develop Eribulin bulk drugs or preparations. The main reason is that Eribulin’s industrial production is extremely difficult.

Everest in the chemical synthesis community


Compared to the soft sponge compound B, although the structure of the modified Eribulin has been greatly simplified, the molecular structure still contains 19 chiral centers, and the synthesis is very difficult. In fact, as of now, Eribulin is still regarded by the industry as the most complex non-peptide drug produced by the purification synthesis method, which is called the Everest of the chemical synthesis industry.


The amount of compound samples required in the early drug research phase is small, and the difficulty to overcome at this stage is the feasibility of the synthetic strategy. Since the macrolide structure framework in the Eribulin structure is identical to the macrolide fragment of halichondrin B, the initial synthetic strategy of Eribulin is based entirely on the total synthesis strategy of halichondrin B. Kishi Laboratories and Eisai’s pharmaceutical chemists worked together to successfully scale up Eribulin at a cost-controllable 62-step reaction, enabling Eribulin to advance smoothly into clinical research.

Although the initial synthetic strategy met the needs of earlier research, the synthetic approach failed to amplify compound synthesis to the gram level. Because preclinical toxicological evaluation has a large demand for sample size, in the second generation of Eribulin synthesis strategy, the medicinal chemist optimizes the key coupling reaction step with lower yield, so that the total yield of the total synthesis is reached. With 17%, Eribulin’s total synthesis reached the gram level for the first time, thus ensuring the demand for clinical research medication.


Although the second-generation Eribulin synthesis strategy meets the needs of clinical research medications, synthetic solutions are still needed for industrial production. There are many problems that need to be solved in this process, such as how to reduce the chromatographic purification step, how to optimize the solvent, reaction temperature and reaction time of the key reaction, so that the amplification synthesis can be performed more efficiently. Moreover, due to the large number of chiral centers in the Eribulin structure, the chiral center control in the synthesis process, qualitative and quantitative analysis of chiral isomers are not easy to solve.


From the full synthesis of the soft sponge, to the structural transformation of Eribulin, to the industrial production of Eribulin, scientists from academia and pharmaceutical companies have turned the natural products from the ocean into drugs that can treat cancer after more than 20 years of exploration. .


The successful launch of Eribulin reflects the new heights that pharmaceutical companies can achieve in chemical synthesis and industrial production, and is an absolute expression of the technical capabilities and R&D capabilities of a pharmaceutical company. After Eisai, which company in China can successfully complete the industrial production of Eribulin and climb the Everest in the chemical synthesis industry?

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